GDC-046 is a Selective and Orally Bioavailable TYK2 Inhibitor

Psoriasis and inflammatory bowel diseases (IBD), both of them are chronic inflammatory diseases. The characterizes of Psoriasis are mainly red and scaly skin plaques. The topical application of corticosteroid is a common treatment for mild diseases, but they are no longer effective for severe forms. IBD is a chronic inflammation of the gastrointestinal tract and colon.

JAK1 is essential for a wide variety of cytokines such as IL-6, TNF-a, et al. Additionally, JAK3 expression mostly exists in hematopoietic cells and exclusively associates with the γc receptor of type I cytokines. Inactivation mutation or deletion of the JAK3 gene in humans or mice often results in severe combined immunodeficiency (SCID).

In this article, we will introduce a TYK2 inhibitor, GDC-046.

GDC-046 is a potent, selective, and orally bioavailable TYK2 inhibitor with Kis of 4.8, 0.7, 0.7, and 0.4 nM for TYK2, JAK1, JAK2, and JAK3, respectively. In cell-based assays, GDC-046 demonstrates reasonable potency in blocking the IL-12 pathway (IL-12 pSTAT4 EC50=380 nM). At the same time, it also displays less activity in the EPO (JAK2) pathway (EPO pSTAT5 EC50=1700 nM), and IL-6 (JAK1) pathway (IL-6 pSTAT3 EC50=2000 nM).
In vivo, In mice, GDC-046 exhibits relatively high clearance (65 mL/min/kg) when dosed intravenously (i.v. 1 mg/kg) and exhibits modest oral exposure (AUC=2.6 μM·h at p.o. 5 mg/kg).
In mice, when GDC-046 treatment with oral administration at 5 mg/ml, it exhibits Clp, t1/2, Vd and F with 21 mL/min/kg, 1.2 hours, 100 L/kg, and 100%,respectively.  Besides, in the rat, it exhibits Clp, t1/2, Vd, and F with 65 mL/min/kg, 0.3 hours, 0.6 L/kg, and 73%, respectively.

Furthermore, Male rats or CD-1 mice are dosed at 1 mg/kg and PO 5 mg/kg as a solution in 60% PEG. It shows statistically significant knockdown of cytokine interferon-γ (IFNγ), in a mouse IL-12 PK/PD model.

In conclusion, GDC-046 exhibits acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in vivo.


Jun Liang, et al. J Med Chem. 2013 Jun 13;56(11):4521-36.